Field of the Invention
This invention relates generally to the field of the treatment of retroviral infections and, more particularly, to the chemotherapeutic treatment of human immunodeficiency virus (HIV) infection and associated disease, including acquired immune deficiency syndrome (AIDS).
Retroviral agents have been implicated in a number of diseases, including cancer, autoimmune disease and AIDS. Human immunodeficiency virus infection causes chronic progressive depletion of CD4+ T lymphocytes (CD4+ cells) and infection of macrophages, resulting in acquired immune deficiency syndrome. Currently zidovudine (AZT), an analogue of thymidine, is the primary anti-viral drug used in the treatment of HIV infection, although two other agents with a similar mechanism of action, dideoxyinosine (ddI) and dideoxycytosine (ddC), are also in clinical trials. Colley, T. P. et al., New Engl. J. Med. (1990)322:1340-45; Fischl, M. A., et al., New Engl. J. Med. (1987)317:185-91. These agents are effective in inhibiting viral replication, and can stabilize the CD4+ cell levels, but they are unable to eliminate one of the major viral reservoirs, HIV infected macrophages. Gartner, S., et al., Science (1986)233:215-19. Severe toxicity, particularly involving HIV host bone marrow is associated with higher doses of zidovudine treatment, and the beneficial effects of the drug in AIDS patients diminishes after prolonged therapy; HIV strains resistant to zidovudine have been observed in treated patients. These findings have prompted the search for alternative drugs for the treatment of HIV infection, particularly agents with a different mechanism of action.
Trichosanthin, derived from the root tuber of Trichosanthes kirilowii belongs to a class of proteins including ricin, momorcharins, and trichokirin, which inhibit ribosome synthesis (ribosomal inhibiting proteins or RIPs) and are cytotoxic for a range of mammalian cells. Kubota, S., et al., Int. J. Peptide Protein Res. (1987)30:646-51; Zhang, X. and Wang, J., Nature (1986)321:477-78; Casellas, P., et al., Eur. J. Biochem. (1988)176:581-88. It is presumed that the mechanism of action involves interaction of the protein with 20S ribosomes, and inhibition of protein synthesis. Theoretically, a single trichosanthin molecule reaching the target site is sufficient to cause cell death. Pharmaceutical grade trichosanthin has been used for many years in China as an abortifacient, and anti-cancer agent for choriocarcinoma. Yeung, H. W., et al., Int. J. Peptide Protein Res. (1988)31:265-68. It was recently reported to inhibit HIV replication in cultured T lymphoblastoid cells and to be specifically cytotoxic for infected monocyte/macrophages. McGrath, M. S., et al., Proc. Natl. Acad. Sci. USA (1989)86:2844- 48. These properties have led to its evaluation for the treatment of HIV infected patients.
Two phase I dose escalation studies using this agent in HIV infected patients have recently been reported. In the first, trichosanthin was obtained from China, and 51 patients with advanced HIV disease were removed from all other drugs and given three weekly doses of trichosanthin at doses ranging from 10 to 30 .mu.g/kg. Dose related side effects were very similar to those seen with other members of this class of compounds, and included reversible hypoalbuminemia. Maximum tolerated dose was 30 .mu.g/kg/dose, and was defined by severe reversible myalgia. A non-dose related side effect was mental status change presenting as reversible dementia, which could progress to coma. This was associated with CD4+ cell levels less than 100/mm.sup.3. Byers, V. S., et al., AIDS (1990)4:1189-96. The second study utilized trichosanthin manufactured in the United States, and treated patients at doses of 5-36 .mu.g/kg as a single injection. Kahn, J. A., et al., AIDS (1990)4:1197-1204. Side effects were quite similar between the two studies, and no evidence of bone marrow toxicity was noted, suggesting that combination therapy with zidovudine and trichosanthin would be well tolerated. In those patients with CD4+ cells over 100/mm.sup.3, who received three doses of drug, a significant increase in CD4+ cell levels was noted. Byers, V. S., et al., AIDS (1990)4:1189-96. The disclosures of all references cited herein are hereby incorporated by reference.